The goal of this Program-Project Grant is to analyze the regulatory processes in eukaryotic cells that guide the cell through a replication cycle and during differentiation toward nonproliferative states. These two focal issues have emerged from our research efforts under the Program-Project Grant CA23076 from the National Cancer Institute, and reflect a consolidation of our interests in those aspects of tumor cell biology that appear most fundamental to an understanding of the cancer states. These aspects appear to be central to achieving the long-range goal of designing effective therapy of human cancer. Six research groups are allied in this progam, led by the independent investigators William F. Dove (PI), Richard R. Burgess, Peggy J. Farham, Michael Hoffmann, Gerald C. Mueller, and Jeffrey Ross. A number of extended collaborative efforts between these groups are proposed, and an even greater number of exchanges of expertise. No Project is an island. With the major effort of each of six research groups joined together in this way, this Program creates a marked efficiency of scale. Some of the questions we shall address are the following: 1. Do specific factors exist that coordinate the transcription of genes whose expression is confined to particular sections of the cell cycle (Farnham, Burgess, Dove)? 2. What are the fundamental and common properties of RNA polymerases and transcriptional complexes that permit the cell cycle and developmental modulation of transcription (Burgess, Farnham, Hoffmann)? 3. What mechanisms operate in the turnover of the mRNAs of interest--and what is their relevance to cell replication control (Ross and Dove); 4. What are the intracellular and intercellular roles played by proto-oncogenes and other developmental genes in embryonic growth and development (Hoffman, Ross, Farnham, Mueller, and Dove)? and 5. What processes operate in the terminal differentiation of representative cell types--and how can such processes be used for more effective cancer therapy (Mueller, Dove, and Hoffman). Accordingly, our Program seeks knowledge on a broad front of processes that control cell replication and differentation, knowledge that is fundamental to the understanding and modulation of normal and malignant cell growth.